What is a Medical Device?

Section 201(h) of the Food, Drugs, and Cosmetics Act defines a medical device as any healthcare product that does not achieve its principal intended purposes by chemical action or metabolized.

Medical Device Classes

• Class I — General Controls — Most exempt from premarket submission.
• Class II — Special Controls — Premarket Notification [510(k)].
• Class III — Premarket Approval — Require Premarket Application [PMA].

510(k) Premarket Notification

• Substantial equivalence.
• 10–15% require clinical data.
• Performance testing.
• Usually confirmatory.
• Type of study dictated by
• The ability of bench and animal testing to answer questions.
• Amount of difference between subject device and predicate.

PMA Premarket Approval Application

• Establish reasonable assurance of safety and effectiveness.
• Bench-Animal-Human.
• Clinical Studies.
• Feasibility and pivotal.

Stages of Review for PMA Device

1. Pre-Sub: Discuss the device design, bench/animal testing, and the clinical trial
2. IDE: Request approval for a clinical trial.
3. PMA: Request market approval.
4. PMA-S: Request approval for device change or upgrade.

What is an Investigational Device Exemption (IDE)?

The FDA approval of an IDE is required for US human study of a significant risk device that is not approved for the study's indication.

Device trials are unique.

• Trials tend to be smaller than drug trials.
• Some novel, many “me-too.”
• Many difficult to blind, randomize, and control.
• Many depend on physician technique.
• Device modifications occur during the trial.
• Endpoints are highly diverse.
• Typically, a single pivotal trial follows the feasibility stage(s).
• Designed to support a “reasonable assurance of safety and effectiveness” for the marketing application.

Types of IDEs

Feasibility Study

• May provide support for a future pivotal study or may be used to answer basic research questions.
• Not intended to be the primary support for a marketing application.
• Endpoints and sample size are generally not statistically driven.
• Often required by the FDA before the pivotal study to assess basic safety and potential for effectiveness.
• Generally ~10–40 patients but may be larger.
• The FDA review is primarily focused on safety and whether the data's potential benefit or value justifies the risk.

Pivotal Study

• Designed to demonstrate a “reasonable assurance of safety and effectiveness. ness.”
• Generally intended as the primary clinical support for a marketing application.
• Endpoints and sample size are statistically driven.
• Designed to assess both safety and effectiveness.
• FDA review is much more complex.

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Basic Submission Elements

Background of medical issue, the study goals, and why this study will further the science.

A Detailed Description of the Device Understudy

• Previous studies (preclinical and clinical).
• Summary of available data.
• Why is a clinical study needed at this stage?
• What evidence supports this study/device's safety and the study data's potential to be meaningful?
• Are there outstanding safety questions that should be addressed with preclinical data?

Risk analysis

Should include:

• What are the potential risks to the patient?
• Does the study mitigate the risks where possible?
• Are the risks outweighed by the potential for benefit and/or value of the study?
• Patient monitoring and follow-up plan.
• Inclusion and exclusion criteria.
• Informed consent document.
• Sample size and the number of investigational centers, with justification.

Submission Elements, Pivotal IDEs

Primary and Secondary Endpoints

Discussion of the appropriateness of endpoint parameters, hypotheses, and success criteria

Basic Trial Design

• Controlled? If not, why not?
•   Randomized? If not, why not?
•   Blinded? If not, why not?

Trial Conduct and Study Monitoring

• Sponsor blinding
• Data handling and adjudication process
• Independent committees
• Case report forms
• Is the right information being gathered to support the study endpoints, and are investigators adequately prompted to report adverse events?

Primary Endpoint Design

Should evaluate the safety and effectiveness of the device in the population expected to be indicated.

• Generally divided into 1 or more “safety” endpoints and 1 or more “effectiveness” endpoints.
• A study will be considered successful if both the safety and effectiveness endpoints are met.
• The clinical protocol should clearly and prospectively detail: — Methods for obtaining endpoint data — Definitions for what will be counted as a primary event in the analysis — Situations in which patient data will be excluded — How missing data will be handled — How the impact of covariates will be assessed.

Sample Size & Follow-Up

Driven by either:

• Primary safety endpoint
• Primary effectiveness endpoint

The minimum number of patients and/or minimum duration of follow-up may be required depending on:

• Understanding of the device's safety and effectiveness  
• concerns regarding the durability of device safety or effectiveness.

Secondary Endpoints

Generally used to evaluate additional meaningful claims.

• Generally only considered if primary endpoints are successful.
• It should be used to provide further insight into the device's effects and mechanisms of action.
• Definitions and analysis methods should be clearly detailed prospectively.
• Not considered “statistically significant” unless a pre-specified alpha allocation plan is in the protocol, even if the p-value is < 0.05.
  

FDA’s IDE Review Decisions

1. Approval — Approves the trial for a specified number of patients and investigational centers.
2. Approval with Conditions — Allows sponsor to begin the trial if the sponsor agrees to address the conditions (deficiencies) from the conditional approval letter within 45 days.
3. Disapproval — The trial may not start until the sponsor addresses the letter's deficiencies, submits this information to the FDA, and receives approval.

Conclusions

One size does not fit all for device trials. Pivotal studies should be designed to evaluate whether there is a “reasonable assurance of safety and effectiveness.” PMA approbation is based upon a Benefit-Risk assessment that strongly considers the outcome of primary safety and effectiveness endpoints. Secondary endpoints are generally used to support claims if the primary endpoints are successful. All endpoint analyses and definitions should be clearly pre-specified in the approved clinical protocol.

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Medical products are safer and more effective for everyone when clinical research includes diverse populations.

Sec. 907 of the Food and Drug Administration Safety and Innovation Act (FDASIA) directed FDA to investigate how well demographic subgroups (sex, age, race, and ethnicity) in applications for medical products — drugs, biologics, and devices, submitted to the agency for marketing approval:

1) Are included in clinical trials; and
2) If subgroup-specific safety and effectiveness data are available.

It is important to test drugs and medical products in the people they are meant to help. The FDA works to ensure that people of different ages, races, ethnic groups, and genders are included in clinical trials. The links below provide information on different populations and their involvement in clinical trials for medical products.

The Office of Minority Health is leading groups made up of many FDA centers to develop actions to reduce health disparities.

• FDASIA Section 907 required the FDA to provide Congress with an action plan detailing “recommendations for improving the completeness and quality of analyses of data on demographic subgroups in summaries of product safety and effectiveness data and labeling; on the inclusion of such data, or the lack of availability of such data, in labeling; and on improving the public availability of such data to patients, health care professionals, and researchers” and to indicate the center(s) tasked with each recommendation. Congress directed the Agency to issue the action plan one year following the Sec. 907 reports publication.
• More information on CERSI (Centers of Excellence in Regulatory Science and Innovation)
• Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data
• Questions and Answers about section 907
• Drug Trials Snapshots: Drug Trials Snapshots provide consumers with information about who participated in clinical trials that supported new drugs' FDA approval. The Snapshots' information also highlights any differences in the benefits and side effects among sex, race, and age groups. Drug Trials Snapshots as part of an overall FDA effort to make demographic data more available and transparent.

More Information on Diversity in Clinical Trials

• Men During Their Reproductive Years
  It gives men who were previously excluded because of potential reproductive harm access to clinical trials to treat life-threatening diseases.
• Women
  See how the FDA and the Office of Women’s Health are working for diversity in clinical trials.
• Minority Health Resources
  See how the FDA Office of Minority Health keeps you informed about; safe medication use, diabetes, food safety, product approvals, HIV/AIDS, and clinical trials.
• Racial/Ethnic Groups
  Reviews the participation of racial or ethnic groups in clinical trials (data from 1995 to 1999).
• NIH Office of Equity, Diversity, and Inclusion
  Sexual and Gender Minority
• Older Adults
  Information on why older adults should participate in clinical trials.
• Children
  A Consumer Update article from January 2010 on children and clinical trials.

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Ontario is a known leader in conducting innovative clinical trials, and the clinical trials community in Ontario has proven this strength throughout the COVID-19 pandemic. One innovative trial underway in Ontario is Vielight Inc.’s COVIDlight trial, which tests whether the recovery of COVID-19 patients may be accelerated by the use of a specialized light therapy device. This trial was made possible in part by Clinical Trials Ontario’s Trial Site Network through a connection made between Vielight Inc. and Impact Clinical Trials. CTO spoke with representatives from Vielight and Impact Clinical Trials about their trial and their experience with the Trial Site Network.

Light Therapy Device for the Treatment of COVID-19

Vielight Inc. has developed a compact and portable device named the “Vielight RX Plus,” based on the science of photobiomodulation (PBM). PBM uses certain light energy to modify cellular functions and can play a role in the management of COVID-19. This clinical trial assesses the efficacy of the Vielight RX Plus to reduce symptom duration and severity in patients suffering from COVID-19.

The Vielight RX Plus device delivers light therapy to the sternum and the nasal canal.

“This device brings a holistic approach to the treatment of COVID-19 patients,”

said Nazanin Hosseinkhah, Research Scientist and Physicist at Vielight Inc.

“The device stimulates the thymus gland, creates nitric oxide, increases natural killer cells, acts as an anti-inflammatory therapy, and increases cellular energy.”

This unique, at-home study has the potential to modulate immune cell and cytokine activity in COVID-19 patients with an easy to use the device.

“We are very hopeful that this trial will prove to help patients recover from COVID-19 at home, and result in less burden to the healthcare system,”

said Hosseinkhah.

Clinical Ttrial

This randomized controlled trial, being managed by Impact Clinical Trials, is actively recruiting 280 participants who are confirmed to have contracted COVID-19. The trial was authorized by Health Canada in early September and is recruiting participants in Ontario and the United States. Participants are allocated into a treatment or a control group, with 140 participants randomized to receive the Vielight RX Plus device and the other 140 participants receiving the current standard of care. The trial is conducted remotely with non-hospitalized participants.

Participants in the treatment group receive the device by courier within 24 hours of registering for the trial. They are asked to place the device on their chest and onto their nostril for 20 mins each day. They then track their symptoms within a daily survey over a 30-day period.

“This is a simple, at-home study for participants to be involved in,”

said Andrea Berk from Impact Clinical Trials.

“Participants in both the treatment and the control groups are completely supported throughout the trial, with a 24-hour number they can call if they have any questions.”

Connections

This trial was made possible in part by a connection made directly through CTO’s Trial Site Network.  The Trial Site Network, part of CTO’s Industry Concierge program, comprises more than 230 sites. The Network allows CTO to provide warm introductions to Ontario’s hospitals, research institutions, private research networks, and CROs.

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“We have been able to guide companies such as Vielight in getting their trials up and running in Ontario,”

said Andrew Haller.

“I was introduced to Andrew Haller from CTO a few months before the COVID-19 pandemic,”

said Berk.

“Pre-COVID I was working on half a dozen connections that had been made through the Trial Site Network. When COVID-19 hit, those projects were put on hold. I reached out to Andrew to let him know Impact Clinical Trials had the consulting capacity, and that is when he introduced us to Vielight.”

Haller knew that Vielight had been searching for someone to take on the management of their clinical trial. “When Andrew introduced us to Andrea Berk from Impact Clinical Trials, we immediately connected and knew they were the right fit,” said Hosseinkhah.

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The International Medical Device Regulators Forum (IMDRF) recognizes that a global approach to auditing and monitoring the manufacturing of medical devices could improve their safety and oversight on an international scale. At its inaugural meeting in Singapore in 2012, the IMDRF identified a workgroup to develop specific documents for advancing a Medical Device Single Audit Program (MDSAP).

What is MDSAP?

The Medical Device Single Audit Program (MDSAP) is a program that conducts a single regulatory audit of a medical device manufacturer’s quality management system that satisfies the requirements of multiple regulatory jurisdictions.

Why was the MDSAP developed?

The MDSAP was developed to enable appropriate regulatory oversight of medical device manufacturers’ quality management systems. The idea is to promote more efficient and flexible use of regulatory resources through work-sharing and mutual acceptance among regulators while respecting the sovereignty of each authority. Also, in the longer term, promote greater alignment of regulatory approaches and technical requirements based on international standards and best practices

Which Regulatory Authorities are part of the MDSAP?

The MDSAP was developed by representatives of the Australian Therapeutic Goods Administration (TGA), Brazil’s Agência Nacional de Vigilância Sanitária (ANVISA), Health Canada, MHLW/PMDA, and the U.S. Food and Drug Administration (FDA). All regulatory authorities participating in the MDSAP are equal partners in the program.

Which manufacturers are eligible for an MDSAP audit?

Any manufacturer of medical devices is eligible. However, each regulatory authority may establish exclusion criteria for some manufacturers. It is important to note that manufacturers that participate in the MDSAP program are responsible for securing and maintaining a contract with an MDSAP recognized auditing organization. In other words, medical device manufacturers are responsible for paying for MDSAP audits conducted by an auditing organization.

Does the MDSAP add requirements for the manufacturer?

No. The MDSAP audit model was developed to cover existing requirements from the Regulatory Authorities participating in the MDSAP. The program does not add any new requirements to existing requirements from ISO 13485.

What are the potential benefits?

1. The MDSAP reduces the overall number of audits or inspections and optimizes the time and resources expended on audit activities.
2. Reduce FDA routine inspections and minimize manufacturing plant and personnel disruptions.
3. Minimize medical device manufacturer disruptions due to multiple regulatory audits.
4. Provide predictable audit schedules (agendas with opening and completion dates).
5. Consistent auditing from a single source for multiple regulatory requirements.
6. As a longer-term goal, it is expected that the program will enhance confidence in the reliability of third-party audits.
7. Some participating regulatory authorities will use MDSAP audit outcomes as an alternative to their own inspections to process applications for medical device marketing authorization.
8. MDSAP may be seen as evidence of a medical device manufacturer’s commitment to quality management systems for product quality and regulatory compliance.

What are the costs associated with MDSAP audits

The cost of conducting an MDSAP audit is dictated by the commercial arrangement between the medical device manufacturer and the authorized MDSAP auditing organization.

COVID-19 Remote Audits

The spread of Covid-19 globally has resulted in the imposition of quarantine orders and travel restrictions that are affecting the ability of auditing organizations to perform MDSAP audits.

On-site audits can only be substituted with remote audits where travel restrictions or social/physical distancing as a result of the pandemic prevent on-site audits from occurring.

In Kaiyan medical, we believe in the benefits of light. We believe in healing without chemicals. With our lights, we want you to have the best version of yourself. More at kaiyanmedical.com

For more detailed information about MDSAP please take a look at their documentation.

Useful links:

1. MDSAP Assessment Procedures and Forms
2. International Medical Device Regulators Forum
3. MDSAP audits during COVID-19
4. Auditing Organization Availability to Conduct MDSAP Audits
5. MDSAP Regulatory Authority Contact Information

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Today's customers expect nothing less than products of the highest quality, and it is incumbent on all manufacturers to assure this expectation is met. A proven technique for checking whether a manufacturing process is in control is a manufacturing audit.

A manufacturing audit is a comprehensive inspection of a process to determine whether it is performing satisfactorily. A manufacturing audit is usually limited to a small portion of units produced, but the manufacturing processes involved are reviewed thoroughly. An audit does not replace normal quality control efforts, but supplements them.

Medical audit is a systematic approach to peer review of medical care in order to identify opportunities for improvement and provide a mechanism for realizing them. Medical audit and clinical audit are often used interchangeably, but clinical audit might be considered to cover all aspects of clinical care-for example, nursing and the role of paramedical staff-whereas medical audit relates to practices initiated directly by doctors. It complements and may partly overlap financial audit, utilization review, and management of resources, but is primarily clinical, not managerial; its focus is the process and results of medical care rather than the use of resources and it is the responsibility of doctors rather than managers.

There are many reasons for conducting a manufacturing audit:

• Assures procedures reflect actual practice (what we say is what we do);
• Uncovers inaccuracies so they can be quickly corrected;
• Reveals the consistency of a process (from person to person, or day to day);
• Demonstrates a proactive approach to process improvement; and
• Encourages ongoing corrective action.

Kaiyan Medical got another audit supplier recognition by Made-in-China. We like to keep our audits and quality standards to the top in order to assure the best experience for our customers and clients

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https://www.bmj.com/content/bmj/299/6697/498.full.pdf

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